rs1194403044

Variant names:

• chr10-86890083-T-C
• rs1194403044
• NM_004329.3:c.89T>C

Your query was ambiguous. Multiple possible variants found:

• chr10-86890083-T-C
• chr10-86890083-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_004329.3(BMPR1A):​c.89T>C​(p.Leu30Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L30R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BMPR1A NM_004329.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.43
• Publications: 0 publications found

Genes affected

BMPR1A (HGNC:1076): (bone morphogenetic protein receptor type 1A) The bone morphogenetic protein (BMP) receptors are a family of transmembrane serine/threonine kinases that include the type I receptors BMPR1A and BMPR1B and the type II receptor BMPR2. These receptors are also closely related to the activin receptors, ACVR1 and ACVR2. The ligands of these receptors are members of the TGF-beta superfamily. TGF-betas and activins transduce their signals through the formation of heteromeric complexes with 2 different types of serine (threonine) kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Type II receptors bind ligands in the absence of type I receptors, but they require their respective type I receptors for signaling, whereas type I receptors require their respective type II receptors for ligand binding. [provided by RefSeq, Jul 2008]

BMPR1A Gene-Disease associations (from GenCC):

• generalized juvenile polyposis/juvenile polyposis coli

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp
• juvenile polyposis syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• polyposis syndrome, hereditary mixed, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hereditary mixed polyposis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart defects, multiple types

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• pulmonary arterial hypertension

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 41 uncertain in NM_004329.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28399646).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004329.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR1A	NM_004329.3	MANE Select	c.89T>C	p.Leu30Pro	missense	Exon 4 of 13	NP_004320.2
	BMPR1A	NM_001406559.1		c.89T>C	p.Leu30Pro	missense	Exon 4 of 14	NP_001393488.1
	BMPR1A	NM_001406560.1		c.89T>C	p.Leu30Pro	missense	Exon 4 of 14	NP_001393489.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR1A	ENST00000372037.8	TSL:1 MANE Select	c.89T>C	p.Leu30Pro	missense	Exon 4 of 13	ENSP00000361107.2
	BMPR1A	ENST00000480152.3	TSL:3	c.89T>C	p.Leu30Pro	missense	Exon 5 of 14	ENSP00000483569.2
	BMPR1A	ENST00000713672.1		c.89T>C	p.Leu30Pro	missense	Exon 3 of 12	ENSP00000518974.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461014 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726840

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5096

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Mar 07, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with proline at codon 30 of the BMPR1A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Jan 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L30P variant (also known as c.89T>C), located in coding exon 2 of the BMPR1A gene, results from a T to C substitution at nucleotide position 89. The leucine at codon 30 is replaced by proline, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.070
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.97	L
PhyloP100		4.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.26
Sift	Benign	0.26	T
Sift4G	Benign	0.35	T
Polyphen		0.088	B
Vest4		0.60
MutPred		0.54		Loss of helix (P = 0.0123)
MVP		0.77
MPC		0.65
ClinPred		0.63	D
GERP RS		4.9
Varity_R		0.19
gMVP		0.97
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1194403044; hg19: chr10-88649840;